Growth is the fundamental physiologic process that characterizes childhood, and adequate nutrition is essential for normal growth. In a rapidly growing child, there is an increased need for “building materials” for the newly synthesized tissues.
Height as a growth parameter is measured as a linear stature at a single point in time compared to expected norms. The norms are typically provided by the general population as depicted in growth charts consisting of a series of percentile curves that illustrate the distribution of selected body measurements in children (for example, the charts of the Centers for Disease Control and Prevention (CDC)). Growth can be worrisome along two variables: height (short stature) and velocity (growth failure).
The American Academy of Pediatrics defines short stature based on height as more than two standard deviations below the average height of the population. A child with short stature is shorter than approximately 97.5% of children of a similar age and gender and typically attains final adult heights of no more than approximately 5′4″ (about 162.5 cm) for boys and 4′11″ (about 150 cm) for girls.
The major cause of growth retardation worldwide is poverty related malnutrition; when suboptimal nutrition is continued for prolonged periods of time, growth stunting occurs as the main clinical phenotype.
Micronutrients are nutrients required only in minute amounts by the human body, but nevertheless play a critical role in the normal growth and development of the body. Deficiencies in micronutrients can lead to a breakdown in numerous bodily functions and result in a plethora of mild to severe disorders. Since the human body is not capable of synthesizing most of the essential micronutrients, the only way to obtain them is through dietary food sources or through supplementation.
The principal micronutrients fall into two categories—vitamins and minerals. Vitamins are essential micronutrients that the body is not capable of synthesizing in sufficient quantities for its growth and maintenance and have to be derived from dietary food sources. However, most vitamins are present only in minute quantities in the foods that we ingest and their bioavailability depends on the food source. There are thirteen essential vitamins of which four, A, D, E, and K are fat soluble and nine, B1, B2, B3, B6, B12, pantothenic acid, biotin, folic acid, and C are water soluble. The fat soluble vitamins are capable of being retained in the body while the water soluble vitamins are excreted from the body.
Minerals which form the second category of micronutrients are inorganic in nature and can be broken down into two sub-categories: macrominerals such as calcium (Ca), phosphorous (P), sodium (Na), potassium (K), magnesium (Mg), and chloride (Cl) and trace minerals such as iron (Fe), zinc (Zn), iodine (Io), selenium (Se), copper (Cu), manganese (Mn), fluoride (fl), chromium (Cr) and molybdenum (Mo). Just as with the essential vitamins, these mineral micronutrients are essential for bodily functions and cannot be synthesized by the body. Therefore, it is necessary to have an adequate intake of these mineral micronutrients from food sources or through supplementation.
Several micronutrients including zinc, iron and vitamin A have been shown to play a critical role in normal growth. The most conclusive evidence to date linking the intake of a specific micronutrient to child growth is for zinc, though the mechanisms by which zinc deficiency impairs growth has not been elucidated. Iron deficiency is associated with anemia and impaired physical growth (Owen G M et al, 1971. Journal of Pediatrics 79:563-568; Rao et al., 1980. Indian J Med Res 71:237-426), but iron supplement alone had no significant effect on child growth (e.g. Ramakrishnan U et al. 2004. Journal of Nutrition 134:2592-2602). Several observational studies reported significant correlations between vitamin A status and stunting (Fawzi W W et al, 1997. Epidemiology 8: 402-407; Kurugol Z et al., 2000. Epidemiology 14:64-69). However, a later Meta analysis by Ramakrishnan et al. (2004, ibid) concluded that vitamin A supplementation interventions had no significant effect on growth.
It has been shown that arginine and lysine, when taken together orally, can increase the release of the body's own stored, natural growth hormone (Isidori A et al. 1981. Current Medical Research and Opinion 7(7):475-481). The effect appeared to be specific to the combination of the two amino acids; neither of the amino acids demonstrated appreciable stimulating activity when administered alone. U.S. Pat. No. 6,346,264 discloses a nutritional supplement for ingestion by humans for restoring growth hormone levels consisting of combinations of amino acids selected from branched chain amino acids chosen from the group leucine, isoleucine, and valine; together with free form amino acids chosen from the group lysine, glutamine, ornithine, arginine, and glycine.
U.S. Patent Application Publication No. 2007/0037861 discloses the use of combination therapy comprising growth hormone (GH) and at least one free fatty acid (FFA) regulator in the treatment of conditions that require or have the potential to require treatment with GH.
Most of the studies which explored the role of specific nutrients in growth and the effect of supplements enriched with these nutrients have focused on malnourished children populations in developing countries (for example, Allen L H et al. 1992. Am J Clin Nutr 56:353-364; Abrams S A et al. 2003. Journal of Nutrition 133:1834-1840).
The effect of a commercially available nutritional composition (PediaSure®) on weight-for-height measurements have been examined in children age 3-5 years with picky-eater behaviors in the Philippines and Taiwan. The supplement, designed to provide complete balanced nutrition for children 1-6 years old and containing 25 vitamins and minerals was given in addition to nutritional counseling, and was shown to enhance both weight and height compared to nutritional counseling alone (Alarcon P A et al. 2003. Clin Pediat 42:209-217). However, the starting point of the participating children was relatively high (below the 25th percentile in weight-for height) and the study ended after 90 days.
Few studies which explored the relations between nutrition and growth were performed in developed countries, where food is not limited. These studies focused on short stature children with idiopathic etiology. These children are often characterized as poor eaters and having a lean body (Wudy S A et al., 2005. Pediatrics 116(1), e52-e57; Thibault H et al., 1993. Horm Res 40 (4):136-140).
Several approaches have been taken for the development of nutritional supplements that can promote healthy development and growth. For example, U.S. Pat. No. 8,287,932 discloses nutritional composition including a lipid or fat; a protein source; at least about 5 mg/100 kcal of a source of long chain polyunsaturated fatty acids which comprises docosahexanoic acid; and at least about 0.2 mg/100 kcal of a prebiotic composition, wherein the prebiotic composition comprises a plurality of oligosaccharides such that the overall fermentation rate profile of the prebiotic composition provides an increased population of beneficial bacteria in the human gut over an extended period of time.
U.S. Patent Application Publication No. 2013/0017182 discloses dietary micronutrient supplement formulations for specific ages, gender, special requirements and health conditions comprising, vitamins, minerals, fish and plant oils, amino acids, enzymes, phytochemicals, herb and fruit extracts and other natural compounds grouped into morning, mid-day and evening formulas based on their synergism and antagonism with each other, their interactions with ingredients in the food consumed during each meal and their bioavailability. The dietary micronutrient formulations are optimized to meet the Recommended Daily Allowances (RDA) and Adequate Intake (AI) standards for each segment of the population with larger amounts of nutrients used in condition-specific formulas.
There is an unmet need for, and would be highly advantageous to have a nutritional supplement specifically designed to enhance the linear growth of pre-pubertal children who are significantly shorter than the norm.